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Characterization of HIV‐1 subtype C I50V and I50L proteases
Author(s) -
BrachoSanchez Edith Rosvely,
Fernandez Marty,
Koch Sandra,
Marzahn Melissa,
Coman Roxana M,
Dunn Ben M
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.675.8
Subject(s) - amprenavir , lopinavir , proteases , atazanavir , virology , protease , ritonavir , biology , medicine , hiv 1 protease , chemistry , human immunodeficiency virus (hiv) , enzyme , viral load , biochemistry , antiretroviral therapy
Last year alone there were approximately 2.5 million new HIV infections; contributing to the total estimate of 33.2 million people infected with HIV worldwide. HIV is classified into different groups, types, subtypes, and recombinant forms. Subtype C alone accounts for 56% of infections. The HIV protease (PR) is crucial in the replication of the virus as it cleaves precursor viral proteins into their mature forms, an essential step in viral maturation. In addition to subtypes and recombinant forms, variability of the HIV PR arises from drug resistance development, as drugs currently used in clinical treatment of HIV include protease inhibitors (PIs). Our studies have focused on introducing the mutations I50L and I50V to the HIV‐1 subtype C PR. These mutations arise upon clinical treatment with the PIs atazanavir and amprenavir, respectively. The mutant PRs have been characterized by both kinetic and crystallographic studies. The HIV‐1 C I50V PR showed an eighteen fold increase in Ki for amprenavir, and an even greater increase in Ki for lopinavir. The HIV‐1 C I50L PR on the other hand, showed a thirteen fold increase in Ki for the PI atazanavir, and a nine fold increase for lopinavir. We have also conducted crystallization studies of both mutant proteases complexed with amprenavir, atazanavir, lopinavir, and topinavir under conditions previously published by our lab. The HIV‐1 C I50V and I50L proteases both diffracted at resolutions of around 2Å. Kinetic data from our studies will hopefully impact clinical treatment of patients with the HIV‐1 C virus. In addition, structural data obtained from the crystallographic studies will have an effect on future drug design.